Advancements in research on the role of the key glycolytic enzyme hexokinase 2 in the regulation of tumor immune evasion (Review)

Tumor metabolic reprogramming is considered to be a critical driver of immune evasion. Hexokinase 2 (HK2), the initial rate-limiting enzyme of the glycolytic pathway, serves a central role in the regulatory network governing tumor metabolism and immune interactions. The expression and modification of HK2 are both influenced by various oncogenic factors and signal transduction pathways, enabling HK2 to mediate immune escape through glycolysis-dependent and independent mechanisms. In this context, HK2 can also interact with the downstream proteins of these oncogenic factors. Furthermore, the high glycolytic activity of tumor cells mediated by HK2 leads to the metabolic reprogramming of immune cells, inhibiting their activation and impairing their function, while releasing high levels of metabolic byproducts that contribute to the formation of immunosuppressive microenvironments. Targeting of metabolic pathways has emerged as a prominent area of research in counteracting immunosuppression. Due to its pivotal role in the glycolysis-driven metabolism-immune axis, HK2 has become an important target for reversing immune escape. Innovative strategies, including subcellular targeted inhibitors and combination immunotherapy, have demonstrated potential in mitigating HK2-driven immunosuppression. The present review provides a comprehensive overview of the intricate immune regulatory mechanisms that involve various signaling pathways, such as phosphatidylinositol 3-kinase/protein kinase B, mitogen-activated protein kinase, nuclear factor κ-light-chain-enhancer of activated B cells, transforming growth factor β, Janus kinase/signal transducer and activator of transcription, and HK2. The present review examines how HK2 enhances antitumor immunity by accelerating the Warburg effect and interacting with diverse immune cell subtypes, thereby contributing to the formation of an acidic, hypoxic and hypoglycemic microenvironment. Furthermore, the present review highlights the potential of HK2 as a therapeutic target and predictive biomarker.